Alternative titles; symbols
HGNC Approved Gene Symbol: EOGT
Cytogenetic location: 3p14.1 Genomic coordinates (GRCh38): 3:68,975,225-69,013,684 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 3p14.1 | Adams-Oliver syndrome 4 | 615297 | Autosomal recessive | 3 |
Protein modification by O-linked-N-acetylglucosamine (O-GlcNAc) regulates intracellular signaling, endocytosis, transcription, and protein stability, and can modulate nutrient sensing. EOGT functions as an O-GlcNAc transferase (EC 2.4.1.255) that modifies threonine residues within epidermal growth factor (EGF; see 131530)-like repeats (summary by Sakaidani et al., 2012).
By database analysis using Drosophila Eogt as query, Sakaidani et al. (2012) identified the mouse, human, and nematode orthologs. Mouse Eogt1 encodes a deduced 527-amino acid protein containing an N-terminal signal peptide and a C-terminal KDEL-like sequence for retention in the endoplasmic reticulum. Northern blot analysis detected variable expression of a major 4.6-kb transcript in all mouse tissues examined, with highest expression in lung and lowest expression in skeletal muscle. Sakaidani et al. (2012) also identified a minor splice variant that includes the 94-basepair intron 12, resulting in a premature stop codon. The truncated protein is predicted to be inactive.
To determine the developmental expression pattern of Eogt, Shaheen et al. (2013) performed whole-mount in situ hybridization on mouse embryos and observed expression of Eogt at embryonic day (E) 10.5 in the growing edge of the limb buds. At E11.5, Eogt mRNA was enriched in the apical ectodermal ridge of the limbs. By E12.5, the expression of Eogt assumed a digit-condensation pattern in the 4 limbs.
Hartz (2012) mapped the EOGT gene to chromosome 3p14.1 based on an alignment of the EOGT sequence (GenBank AK091089) with the genomic sequence (GRCh37).
Using an in vitro assay, Sakaidani et al. (2012) found that mouse Eogt utilized uridine diphosphate (UDP)-GlcNAc as a sugar donor to transfer GlcNAc to a conserved threonine residue within the EGF-like domain of Notch (see 190198). Enzyme activity was enhanced in the presence of divalent cations, particularly Mn(2+). In transfected HEK293 cells, the O-GlcNAc moiety was further modified into an elongated glycan capped by N-acetyl-lactosamine.
In affected individuals from 3 consanguineous Arab families with Adams-Oliver syndrome mapping to chromosome 3 (AOS4; 615297), Shaheen et al. (2013) identified homozygosity for 2 missense mutations and a 1-bp deletion, respectively (614789.0001-614789.0003). The variants segregated with disease in the families and were not found in 230 Saudi exomes, the 1000 Genomes Project, or the NHLBI Exome Variant Server.
In a Turkish boy and his father with AOS4 from a multiconsanguineous family, Schroder et al. (2019) identified a homozygous missense mutation in the EOGT gene (C135Y; 614789.0004). In a German man with AOS4, they identified a homozygous splicing mutation (614789.0005) in the EOGT gene. The man's parents were heterozygous for the mutation.
Sakaidani et al. (2012) found that depletion of Eogt in developing Drosophila wing discs caused cell adhesion defects and resulted in wing blistering in the posterior compartment. The phenotype was completely rescued by expression of mouse Eogt1, indicating conservation of function.
In a 5-week-old Arab girl with Adams-Oliver syndrome (AOS4; 615297), who was born of first-cousin parents, Shaheen et al. (2013) identified homozygosity for a c.620G-C transversion in the EOGT gene, resulting in a trp207-to-ser (W207S) substitution at a highly conserved residue. Her unaffected parents were heterozygous carriers of the mutation, which was not found in 230 Saudi exomes, the 1000 Genomes Project, or the NHLBI Exome Variant Server. In addition to cutis aplasia of the scalp and terminal transverse defects of her toes, she had an atrial septal defect (ASD-II), but she had no microphthalmia and neuroimaging was normal.
In a 2.67-year-old Arab boy with Adams-Oliver syndrome (AOS4; 615297), who was born of consanguineous parents, Shaheen et al. (2013) identified homozygosity for a 1-bp deletion (c.1074delA) in the EOGT gene, causing a frameshift that resulted in a premature stop codon (Gly359AspfsTer28). The mutation was not found in 230 Saudi exomes, the 1000 Genomes Project, or the NHLBI Exome Variant Server. In addition to cutis aplasia of the scalp and terminal transverse defects of the toes that were more pronounced on the right, he had a muscular ventricular septal defect and patent ductus arteriosus, which had resolved. Additional features included left temporal and occipital lobe infarcts of presumed prenatal origin, speech and fine motor delays, and umbilical hernia. Shaheen et al. (2013) stated that using the alternatively spliced NCBI version of EOGT (GenBank NM_173654.1), the mutation would be designated 832-791delA.
In 3 affected children from a consanguineous Arab kindred with Adams-Oliver syndrome (AOS4; 615297), Shaheen et al. (2013) identified homozygosity for a c.1130G-A transition in the EOGT gene, resulting in an arg377-to-gln (R377Q) substitution at a highly conserved residue. The unaffected parents were heterozygous for the mutation, which was not found in 230 Saudi exomes, the 1000 Genomes Project, or the NHLBI Exome Variant Server. The 3 affected individuals had cutis aplasia of the scalp and terminal transverse defects of the toes, but no microphthalmia or cardiac anomalies. The 3-year-old female proband also exhibited cutis marmorata, 6 cafe-au-lait patches on her chest and abdomen, and a small umbilical hernia. Shaheen et al. (2013) stated that using the alternatively spliced NCBI version of EOGT (GenBank NM_173654.1), the mutation would be designated c.878G-A, ARG293GLN.
In a 10-year-old boy with Adams-Oliver syndrome (AOS4; 615297) from a multiconsanguineous Turkish family, Schroder et al. (2019) identified a homozygous c.404G-A transition (c.404G-A, NM_001278689.1) in the EOGT gene, resulting in a cys135-to-ter (C135Y) substitution at a highly conserved residue. The mutation was identified by whole-exome sequencing and confirmed by Sanger sequencing. The patient's father, who had a hairless, scarred area on his scalp, was also found to be homozygous for the mutation. The variant was present in 1 in 249,292 alleles in the gnomAD database. Functional studies were not performed.
In a 24-year-old German man with Adams-Oliver syndrome (AOS4; 615297), Schroder et al. (2019) identified a homozygous splice site mutation (c.311+1G-T, NM_001278689.1) in the EOGT gene, predicted to lead to abnormal splicing of exon 5. The mutation, which was identified by whole-exome sequencing and confirmed by Sanger sequencing, was present in heterozygous state in the parents. The variant was present in 6 of 251,330 alleles in the gnomAD database. Functional studies were not performed. A sib of the patient, who had a large area of cutis aplasia with bony defects of the scalp, was stillborn at 31 weeks' gestation, but genetic testing was not performed.
Hartz, P. A. Personal Communication. Baltimore, Md. 8/27/2012.
Sakaidani, Y., Ichiyanagi, N., Saito, C., Nomura, T., Ito, M., Nishio, Y., Nadano, D., Matsuda, T., Furukawa, K., Okajima, T. O-linked-N-acetylglucosamine modification of mammalian Notch receptors by an atypical O-GlcNAc transferase Eogt1. Biochem. Biophys. Res. Commun. 419: 14-19, 2012. [PubMed: 22310717] [Full Text: https://doi.org/10.1016/j.bbrc.2012.01.098]
Schroder, K. C., Duman, D., Tekin, M., Schanze, D., Sukalo, M., Meester, J., Wuyts, W., Zenker, M. Adams-Oliver syndrome caused by mutations of the EOGT gene. Am. J. Med. Genet. 179A: 2246-2251, 2019. [PubMed: 31368252] [Full Text: https://doi.org/10.1002/ajmg.a.61313]
Shaheen, R., Aglan, M., Keppler-Noreuil, K., Faqeih, E., Ansari, S., Horton, K., Ashour, A., Zaki, M. S., Al-Zahrani, F., Cueto-Gonalez, A. M., Abdel-Salam, G., Temtamy, S., Alkuraya, F. S. Mutations in EOGT confirm the genetic heterogeneity of autosomal-recessive Adams Oliver syndrome. Am. J. Hum. Genet. 92: 598-604, 2013. [PubMed: 23522784] [Full Text: https://doi.org/10.1016/j.ajhg.2013.02.012]